Method for inhibiting neoplastic cells and related conditions by exposure to 4-aminoquinazoline derivatives

ABSTRACT

A method for inhibiting neoplastic cells and related conditions by exposing them to 4-aminoquinazoline derivatives.

[0001] This application is a Continuation of prior U.S. application Ser.No. 09/060,444 filed Apr. 15, 1998 entitled “Method for InhibitingNeoplastic Cells and Related Conditions by Exposure to4-Aminoquinazoline Derivatives” which is incorporated herein byreference.

TECHNICAL FIELD

[0002] This invention relates to a method for the selective inhibitionof neoplastic cells, for example, for the treatment or prevention ofprecancerous lesions or other neoplasias in mammals.

BACKGROUND OF THE INVENTION

[0003] Each year in the United States alone, untold numbers of peopledevelop precancerous lesions, which is a form of neoplasia, as discussedbelow. Such lesions exhibit a strong tendency to develop into malignanttumors, or cancer. Such lesions include lesions of the breast (that candevelop into breast cancer), lesions of the skin (that can develop intomalignant melanoma or basal cell carcinoma), colonic adenomatous polyps(that can develop into colon cancer), and other such neoplasms.Compounds that prevent or induce the remission of existing precancerousor cancerous lesions or carcinomas would greatly reduce illness anddeath from cancer.

[0004] For example, approximately 60,000 people die from colon cancer,and over 150,000 new cases of colon cancer are diagnosed each year. Forthe American population as a whole, individuals have a six percentlifetime risk of developing colon cancer, making it the second mostprevalent form of cancer in the country. Colon cancer is also prevalentin Western Europe. It is believed that increased dietary fat consumptionis increasing the risk of colon cancer in Japan.

[0005] In addition, the incidence of colon cancer reportedly increaseswith age, particularly after the age of 40. Since the mean ages ofpopulations in America and Western Europe are increasing, the prevalenceof colorectal cancer should increase in the future.

[0006] To date, little progress has been made in the prevention andtreatment of colorectal cancer, as reflected by the lack of change inthe five-year survival rate over the last few decades. The only cure forthis cancer is surgery at an extremely early stage. Unfortunately, mostof these cancers are discovered too late for surgical cure. In manycases, the patient does not experience symptoms until the cancer hasprogressed to a malignant stage.

[0007] In view of these grim statistics, efforts in recent years haveconcentrated on colon cancer prevention. Colon cancer usually arisesfrom pre-existing benign neoplastic growths known as polyps. Preventionefforts have emphasized the identification and removal of colonicpolyps. Polyps are identified by x-ray and/or colonoscopy, and usuallyremoved by devices associated with the colonoscope. The increased use ofcolon x-rays and colonoscopies in recent years has detected clinicallysignificant precancerous polyps in four to six times the number ofindividuals per year that acquire colon cancer. During the past fiveyears alone, an estimated 3.5 to 5.5 million people in the United Stateshave been diagnosed with adenomatous colonic polyps, and it is estimatedthat many more people have or are susceptible to developing thiscondition, but are as yet undiagnosed. In fact, there are estimates that10-12 percent of people over the age of 40 will form clinicallysignificant adenomatous polyps.

[0008] Removal of polyps has been accomplished either with surgery orfiber-optic endoscopic polypectomy—procedures that are uncomfortable,costly (the cost of a single polypectomy ranges between $1,000 and$1,500 for endoscopic treatment and more for surgery), and involve asmall but significant risk of colon perforation. Overall, about $2.5billion is spent annually in the United States in colon cancer treatmentand prevention.

[0009] In the breast, breast cancer is often treated surgically, oftenby radical mastectomy with its painful aftermath. Such surgery iscostly, too.

[0010] As indicated above, each lesion carries with it a chance that itwill develop into a cancer. The likelihood of cancer is diminished if aprecancerous lesion is removed. However, many of these patientsdemonstrate a propensity for developing additional lesions in thefuture. They must, therefore, be monitored periodically for the rest oftheir lives for reoccurrence.

[0011] In most cases (i.e. the cases of sporadic lesion formation, e.g.so-called common sporadic polyps), lesion removal will be effective toreduce the risk of cancer. In a small percentage of cases (i.e. caseswhere numerous lesions form, e.g. the so-called polyposis syndromes),removal of all or part of the effected area (e.g. the colon) isindicated. For example, the difference between common sporadic polypsand polyposis syndromes is dramatic. Common sporadic polyp cases arecharacterized by relatively few polyps which can usually be removedleaving the colon intact. By contrast, polyposis syndrome cases can becharacterized by many (e.g. hundreds or more) of polyps—literallycovering the colon in some cases—making safe removal of the polypsimpossible short of surgical removal of the colon.

[0012] Because each lesion carries with it a palpable risk of cancerousdevelopment, patients who form many lesions (e.g. polyposis syndromepatients) invariably develop cancer if left untreated. Surgical removalof the colon is the conventional treatment in polyposis patients. Manypolyposis patients have undergone a severe change in lifestyle as aresult of the disfiguring surgery. Patients have strict dietaryrestrictions, and many must wear ostomy appliances to collect theirintestinal wastes.

[0013] The search for drugs useful for treating and preventing cancer isintensive. Indeed, much of the focus of cancer research today is on theprevention of cancer because chemotherapy for cancer itself is often noteffective and has severe side effects. Cancer chemoprevention isimportant for recovered cancer patients who retain a risk of cancerreoccurrence. Also, cancer prevention is important for people who havenot yet had cancer, but have hereditary factors that place them at riskof developing cancer. With the development of new genetic screeningtechnologies, it is easier to identify those patients with high-riskgenetic factors, such as the potential for polyposis syndrome, who wouldgreatly benefit from chemopreventative drugs. Therefore, finding suchanti-cancer drugs that can be used for prolonged preventive use is ofvital interest.

[0014] Known chemopreventative and chemotherapeutic drugs are believedto kill cancer cells by inducing apoptosis, or as sometimes referred toas “programmed cell death.” Apoptosis naturally occurs in virtually alltissues of the body, and especially in self-renewing tissues such asbone marrow, gut, and skin. Apoptosis plays a critical role in tissuehomeostasis, that is, it ensures that the number of new cells producedare correspondingly offset by an equal number of cells that die. Forexample, the cells in the intestinal lining divide so rapidly that thebody must eliminate cells after only three days in order to prevent theovergrowth of the intestinal lining.

[0015] Recently, scientists have realized that abnormalities ofapoptosis can lead to the formation of precancerous lesions andcarcinomas. Also, recent research indicates that defects in apoptosisplay a major role in other diseases in addition to cancer. Consequently,compounds that modulate apoptosis could be used to prevent or controlcancer, as well as used in the treatment of other diseases.

[0016] Unfortunately, even though known chemotherapeutic drugs mayexhibit such desirable apoptosis effects, most chemotherapeutic drugshave serious side effects that prohibit their long-term use, or use inotherwise healthy individuals with precancerous lesions. These sideeffects, which are a result of the high levels of cytotoxicity of thedrugs, include hair loss, weight loss, vomiting, immune suppression andother toxicities. Therefore, there is a need to identify new drugcandidates for therapy that do not have such serious side effects inhumans.

[0017] In recent years, several non-steroidal anti-inflammatory drugs(“NSAIDs”), originally developed to treat arthritis, have showneffectiveness in inhibiting and eliminating colonic polyps. Polypsvirtually disappear when the patients take the drug, particularly whenthe NSAID sulindac is administered. However, the prophylactic use ofcurrently available NSAIDs, even in polyposis syndrome patients, ismarked by severe side reactions that include gastrointestinalirritations and ulcerations. Once NSAID treatment is terminated due tosuch complications, the polyps return, particularly in polyposissyndrome patients.

[0018] Sulindac has been particularly well received among the NSAIDs forthe polyp treatment. Sulindac is a sulfoxide compound that itself isbelieved to be inactive as an anti-arthritic agent. The sulfoxide isreportedly converted by liver enzymes to the corresponding sulfide,which is acknowledged to be the active moiety as a prostaglandinsynthesis inhibitor. The sulfide, however, is associated with the sideeffects of conventional NSAIDs. The sulfoxide is also known to bemetabolized to sulfone compound that has been found to be inactive as aninhibitor of prostaglandin synthesis but active as an inhibitor ofprecancerous lesions.

SUMMARY OF THE INVENTION

[0019] This invention includes a method of inhibiting neoplastic cellsby exposing those cells to a pharmacologically effective amount of thosecompounds described below. Such compounds are effective in modulatingapoptosis and eliminating and inhibiting the growth of neoplasias suchas precancerous lesions.

[0020] The compounds that are useful in the methods of this inventioninclude those of Formula I:

[0021] wherein

[0022] R₁ is hydrogen or C1-4 alkyl;

[0023] Y is C1-6 alkylene; A is -O-R₀ or -S(O)_(p)-R₀,

[0024] R₀ is C1-4 alkyl-hydroxy;

[0025] p is 0-2;

[0026] Z is single bond, methylene, ethylene (CH₂CH₂), vinylene (CH═CH)or ethynylene (C═C);

[0027] CyB is:

[0028] (1) 7-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one, two or three nitrogenatoms,

[0029] (2) 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, two or three nitrogen atoms,

[0030] (3) 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one nitrogen atom,

[0031] (4) 4-or 5-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one, two or threenitrogen atoms, or

[0032] (5) 4-7 membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one or two oxygen atoms, or oneor two sulfur atoms;

[0033] R₃ is hydrogen, C1-4 alkyl, C1-4 alkoxy, halogen ortrifluoromethyl;

[0034] R₄ is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) —COOR₈,in which R₈ is hydrogen or C1-4 alkyl, (5) —NR₉R₁₀, (6) —NHCOR₁₁, (7)—NHSO₂R₁₁, (8) SO₂NR₉R₁₀, (9) —OCOR₁₁, (10) halogen, (11)trifluoromethyl, (12) hydroxy, (13) nitro, (14) cyano, (15) —SO₂N═CHNR₁₁R₁₀, (16) —CONR₁₂R₁₃, (17) C1-4 alkylthio, (18) C1-4 alkylsulfinyl,(19) C1 -4 alkylsulfonyl, (20) ethynyl, (21) hydroxymethyl, (22)tri(C1-4 alkyl) silylethynyl or (23) acetyl; and m and n independentlyare 1 or 2; with the proviso that a CyB ring should not bond to Zthrough a nitrogen atom in the CyB ring when Z is vinylene orethynylene;

[0035] R₉ is hydrogen, C1-4 alkyl or phenyl(C1-4 alkyl);

[0036] R₁₀ is hydrogen or C1-4 alkyl;

[0037] R₁₁ is C1-4 alkyl;

[0038] R₁₂ is hydrogen or C1-4 alkyl;

[0039] R₁₃ is C1-4 alkyl or phenyl(C1-4 alkyl);

[0040] or pharmaceutically acceptable acid addition salts,pharmaceutically acceptable salts, or hydrates thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0041] As discussed above, this invention involves the use of compoundsdescribed above for treating patients with neoplasia, for examplecancerous or precancerous lesions.

[0042] As used herein, the term “C 1-4 alkyl” means methyl, ethyl,propyl, butyl and the isomers thereof. The term “C1-4 alkyl-hydroxy”means 1 -hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyland the isomers thereof. The term “C1-4 alkoxy” means methoxy, ethoxy,propoxy, butoxy and isomers thereof.

[0043] As used herein the term “halogen” means fluorine, chlorine,bromine and iodine. The term “C1-6 alkylene” means methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof.

[0044] In Formula (I), examples of 7-membered, unsaturated or partiallysaturated, monocyclic hetero ring containing as hetero atoms, one, twoor three nitrogen atoms, represented by CyB-(1), are azepine, diazepine,triazepine, and partially saturated rings thereof.

[0045] Examples of 6-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, two or three nitrogenatoms, represented by CyB-(2) are pyridazine, pyrimidine, pyrazine,triazine, and partially saturated rings thereof.

[0046] Examples of 6-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one nitrogen atom,represented by CyB-(3), are pyridine, dihydropyridine, andtetrahydropyridine.

[0047] Examples of 4- or 5-membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one, two or threenitrogen atoms, represented by CyB-(4), are pyrrole, imidazole,pyrazole, triazole, azetine, and partially saturated rings thereof,

[0048] Examples of 4-7 membered, unsaturated or partially saturated,monocyclic hetero ring containing as hetero atoms, one or two oxygenatoms, or one or two sulfur atoms represented by CyB-(5), are thiophene,furan, thiain, pyran, dithiain, dioxin, dioxole, and partially saturatedrings thereof.

[0049] Preferably, such compounds are administered without therapeuticamounts of an NSAID.

[0050] The present invention is also a method of treating mammals withprecancerous lesions by administering a pharmacologically effectiveamount of an pharmaceutical composition (preferably enterically coated)that includes compounds of Formula I. In still another form, theinvention is a method of inducing apoptosis in human cells by exposingthose cells to an effective amount of compounds of formula I, wherein R₁through R₆ to those cells sensitive to such a compound.

[0051] As used herein, the term “precancerous lesion” includes syndromesrepresented by abnormal neoplastic, including dysplastic, changes oftissue. Examples include adenomatous growths in colonic, breast or lungtissues, or conditions such as dysplastic nevus syndrome, a precursor tomalignant melanoma of the skin. Examples also include, in addition todysplastic nevus syndromes, polyposis syndromes, colonic polyps,precancerous lesions of the cervix (i.e., cervical dysplasia), prostaticdysplasia, bronchial dysplasia, breast, bladder and/or skin and relatedconditions (e.g., actinic keratosis), whether the lesions are clinicallyidentifiable or not.

[0052] As used herein, the term “carcinomas” refers to lesions that arecancerous. Examples include malignant melanomas, breast cancer, andcolon cancer.

[0053] As used herein, the term “neoplasm” refers to both precancerousand cancerous lesions as well as hyperplastic conditions.

[0054] Compounds useful in the methods of this invention may beformulated into compositions together with pharmaceutically acceptablecarriers for oral administration in solid or liquid form, or for rectalor topical administration, although carriers for oral administration aremost preferred.

[0055] Pharmaceutically acceptable carriers for oral administrationinclude capsules, tablets, pills, powders, troches and granules. In suchsolid dosage forms, the carrier can comprise at least one inert diluentsuch as sucrose, lactose or starch. Such carriers can also comprise, asis normal practice, additional substances other than diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, troches and pills, the carriers may also comprise bufferingagents. Carriers such as tablets, pills and granules can be preparedwith enteric coatings on the surfaces of the tablets, pills or granules.Alternatively, the enterically coated compound can be pressed into atablet, pill, or granule, and the tablet, pill or granules foradministration to the patient. Preferred enteric coatings include thosethat dissolve or disintegrate at colonic pH such as shellac or EudragetS.

[0056] Pharmaceutically acceptable carriers include liquid dosage formsfor oral administration, e.g. pharmaceutically acceptable emulsions,solutions, suspensions, syrups and elixirs containing inert diluentscommonly used in the art, such as water. Besides such inert diluents,compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring andperfuming agents.

[0057] Pharmaceutically acceptable carriers for rectal administrationare preferably suppositories that may contain, in addition to thecompounds of Formula I, excipients such as cocoa butter or a suppositorywax.

[0058] The pharmaceutically acceptable carrier and compounds of thisinvention are formulated into unit dosage forms for administration to apatient. The dosage levels of active ingredient (i.e. compounds of thisinvention) in the unit dosage may be varied so as to obtain an amount ofactive ingredient effective to achieve lesion-eliminating activity inaccordance with the desired method of administration (i.e., oral orrectal). The selected dosage level therefore depends upon the nature ofthe active compound administered, the route of administration, thedesired duration of treatment, and other factors. If desired, the unitdosage may be such that the daily requirement for active compound is inone dose, or divided among multiple doses for administration, e.g., twoto four times per day.

[0059] The pharmaceutical compositions of this invention are preferablypackaged in a container (e.g. a box or bottle, or both) with suitableprinted material (e.g. a package insert) containing indications,directions for use, etc.

[0060] The synthesis of compounds useful in practicing this invention isdescribed in U.S. Pat. No. 5,439,985 as shown in the following.According to the present invention, of the compounds of the presentinvention, the compounds of the formula:

[0061] wherein R₄₁ is (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4)—COOR₈, (5) —NR₉₁ R₁₀₁, in which R₉₁ is hydrogen, C1-4 alkyl orphenyl(C1-4 alkyl) and R₁₀₁, is hydrogen or C1-4 alkyl, provided thatboth R₉₁ and R₁₀₁ are not hydrogen, (6) SO₂NR₉ R₁₀, in which R₉ and R₁₀are as hereinbefore defined, (7) halogen, (8) trifluoromethyl, (9)nitro, (10) cyano, (11) C1-4 alkylthio, (12) tri(C1-4 alkyl)silylethynyl, (13) —SO₂N═CHNR₁₁ R₁₀, in which R₁₁ and R₁₀ are the samemeaning as hereinbefore defined, or (14) —CONR₁₂ R₁₃, in which R₁₂ andR₁₃ are the same meaning as hereinbefore defined, CyB₁ is ashereinbefore defined for CyB, provided that a carbon atom in the ringshould bond to Z, and the other symbols are as hereinbefore defined; andthe compounds of the formula:

[0062] wherein Z_(1,) is single bond or methylene, CyB₂ is ashereinbefore defined for CyB, provided that a nitrogen atom in the ringshould bond to Z₁, and the other symbols are as hereinbefore defined;may be prepared by using a series of reactions depicted in Scheme A andB, respectively, wherein R₅₀ is C1-4 alkyl and the other symbols are ashereinbefore defined.

[0063] Each reaction in Scheme A and B may be carried out by methodsknown per se, under conditions described therein.

[0064] For example, the compounds of the formula (IA) may be preparedfrom those of Formula (V) by the reaction with an amine of Formula (IX)in a proper organic solvent such as a lower alkanol (e.g. ethanol) ortetrahydrofuran, or a mixture thereof, at a temperature from ambient toreflux, for several hours to several days, if necessary in the presenceof a base such as triethylamine.

[0065] Further, the compounds of the formula (IB) may be prepared fromthose of the formula (XII) by the reaction with a cyclic amine ofFormula (XVI) in phenol at a reflux temperature for several hours.

[0066] Furthermore, the compounds of the present invention, of Formula:

[0067] wherein the various symbols are as defined above; may be preparedfrom those of Formula:

[0068] wherein the various symbols are as defined previously; by themethods described above for the conversion of the compounds of Formula(V) into those of Formula (IA). The compounds of Formula (XVII) may beprepared by the methods similar to those described in Scheme A.

[0069] On the other hand, the compounds of Formula I other than those ofFormulae (IA), (IB) and (IC) may be prepared by the methods known per sedescribed below.

[0070] The compounds of Formula (I) wherein R₄ is amino may be preparedfrom those wherein R₄ is nitro, by the reduction with zinc etc. in aproper organic solvent.

[0071] The compounds of Formula (I) wherein R₄ is hydroxy may beprepared from those wherein R₄ is alkoxy such as methoxy, by thereaction with hydrogen bromide or tribromoboron.

[0072] The compounds of Formula (I) wherein R₄ is —NHCOR₁₁, wherein R₁₁is as defined above, may be prepared from those wherein R₄ is nitro, bythe reaction with the corresponding organic acid such as acetic acid inthe presence of zinc dust.

[0073] The compounds of Formula (I) wherein R₄ is NHSO₂R₁₁, wherein R₁₁is as defined above, may be prepared from those wherein R4 is amino bythe reaction with the corresponding alkylsulfonyl chloride such asmethanesulfonyl chloride.

[0074] The compounds of Formula (I) wherein R₄ is —OCOR₁₁, wherein R₁₁is as hereinbefore defined, may be prepared from those wherein R₄ ishydroxy by the esterification with the corresponding organic acid suchas acetic acid.

[0075] The compounds of Formula (I) wherein R₄ is C1-4 alkylsulfinyl orC1-4 alkylsulfonyl may be prepared from those wherein R₄ is C1-4alkylthio by the oxidation by oxidating agent such as hydrogen peroxide.

[0076] The compounds of Formula (I) wherein R₄ is hydroxymethyl may beprepared from those wherein R₄ is alkyoxycarbonyl, by the reduction withreducing agent such as lithium borohydride, lithium aluminum hydrideetc.

[0077] The compounds of Formula (I) wherein R₄ is ethynyl may beprepared from those wherein R₄ is tri(C1-4 alkyl)silylethynyl, by theremoval reaction of silyl group with tetrabutylammonium halide.

[0078] The compounds of Formula (I) wherein R₄ is acetyl may be preparedfrom those wherein R₄ is ethynyl, by the reaction with mercury sulfateand acetic acid in an acidic condition.

[0079] In each reaction in the present specification, products may bepurified by conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

[0080] The starting materials of Formulae (II), (VI) and (XIII), andeach reagents of Formulae (VII), (VIII), (IX), (XV), (XVI), (XVII) and(XVIII) used in the process for the preparation of the present inventionare known per se or may be easily prepared by known methods.

[0081] Examples of representative compounds of the present invention arelisted as follows:

[0082] 1 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(6-methyl-3-pyrdyl)quinazoline,

[0083] 24-(2-(2-hydroxyethoxy)ethyl)amino-2-(6-methoxy-3-pyridyl)quinazoline,

[0084] 3 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(6-chloro-3-pyridyl)quinazoline,

[0085] 4 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(6-trifluoromethyl-3-pyridyl)quinazoline,

[0086] 54-(2-(2-hydroxyethoxy)ethyl)amino-6-methyl-2-(3-pyridyl)quinazoline,

[0087] 64-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(3-pyridyl)quinazoline,

[0088] 74-(2-(2-hydroxyethoxy)ethyl)amino-6,7-dimethoxy-2-(3-pyridyl)quinazoline,

[0089] 84-(2-(2-hydroxyethoxy)ethyl)amino-6-carboxy-2-(3-pyridyl)quinazoline,

[0090] 9 4-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(3-pyridyl)quinazoline,

[0091] 104-(2-(2-hydroxyethoxy)ethyl)amino-6-amino-2-(3-pyridyl)quinazoline,

[0092] 114-(2-(2-hydroxyethoxy)ethyl)amino-6-(N,N-dimethylamino)-2-(3-pyridyl)quinazoline,

[0093] 124-(2-(2-hydroxyethoxy)ethyl)amino-6-acetylamino-2-(3-pyridyl)quinazoline,

[0094] 134-(2-(2-hydroxyethoxy)ethyl)amino-6-methanesulfonylamino-2-(3-pyridyl)quinazoline,

[0095] 144-(2-(2-hydroxyethoxy)ethyl)amino-6-sulfamoyl-2-(3-pyridyl)quinazoline,

[0096] 154-(2-(2-hydroxyethoxy)ethyl)amino-6-acetoxy-2-(3-pyridyl)quinazoline,

[0097] 164-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-(3-pyridyl)quinazoline,

[0098] 174-(2-(2-hydroxyethoxy)ethyl)amino-6-bromo-2-(3-pyridyl)quinazoline,

[0099] 184-(2-(2-hydroxyethoxy)ethyl)amino-7-fluoro-2-(3-pyridyl)quinazoline,

[0100] 194-(2-(2-hydroxyethoxy)ethyl)amino-6-trifiuoromethyl-2-(3-pyridyl)quinazoline,

[0101] 204-(2-(2-hydroxyethoxy)ethyl)amino-6-hydroxy-2-(3-pyridyl)quinazoline,

[0102] 214-(2-(2-hydroxyethoxy)ethyl)amino-6-nitro-2-(3-pyridyl)quinazoline,

[0103] 224-(2-(2-hydroxyethoxy)ethyl)amino-6-cyano-2-(3-pyridyl)quinazoline,

[0104] 234-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-(3-pyridyl)quinazoline,

[0105] 244-(2-(2-hydroxyethoxy)ethyl)amino-6-methyl-2-(4-pyridyl)quinazoline,

[0106] 254-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(4-pyridyl)quinazoline,

[0107] 264-(2-(2-hydroxyethoxy)ethyl)amino-6,7-dimethoxy-2-(4-pyridyl)quinazoline,

[0108] 274-(2-(2-hydroxyethoxy)ethyl)amino-6-carboxy-2-(4-pyridyl)quinazoline,

[0109] 284-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(4-pyridyl)quinazoline,

[0110] 294-(2-(2-hydroxyethoxy)ethyl)amino-6-amino-2-(4-pyridyl)quinazoline,

[0111] 304-(2-(2-hydroxyethoxy)ethyl)amino-6-(N,N-dimethylainino)-2-(4-pyridyl)quinazoline,

[0112] 314-(2-(2-hydroxyethoxy)ethyl)amino-6-acetylamino-2-(4-pyridyl)quinazoline,

[0113] 324-(2-(2-hydroxyethoxy)ethyl)amino-6-methanesulfonylamino-2-(4-pyridyl)quinazoline,

[0114] 334-(2-(2-hydroxyethoxy)ethyl)amino-6-sulfamoyl-2-(4-pyridyl)quinazoline,

[0115] 344-(2-(2-hydroxyethoxytethyl)amino-6-acetoxy-2-(4-pyridyl)quinazoline,

[0116] 354-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-(4-pyridyl)quinazoline,

[0117] 364-(2-(2-hydroxyethoxy)ethyl)amino-6-bromo-2-(4-pyridyl)quinazoline,

[0118] 374-(2-(2-hydroxyethoxy)ethyl)amino-7-fluoro-2-(4-pyridyl)quinazoline,

[0119] 384-(2-(2-hydroxyethoxy)ethyl)amino-6-trifluoromethyl-2-(4-pyridyl)quinazoline,

[0120] 394-(2-(2-hydroxyethoxy)ethyl)amino-6-hydroxy-2-(4-pyridyl)quinazoline,

[0121] 404-(2-(2-hydroxyethoxy)ethyl)amino-6-nitro-2-(4-pyridyl)quinazoline,

[0122] 414-(2-(2-hydroxyethoxy)ethyl)amino-6-cyano-2-(4-pyridyl)quinazoline,

[0123] 424-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-(4-pyridyl)quinazoline,

[0124] 434-(2-(2-hydroxyethoxy)ethyl)amino-6-methyl-2-(1-imidazolyl)quinazoline,

[0125] 44 4-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,

[0126] 454-(2-(2-hydroxyethoxy)ethyl)amino-6,7-dimethoxy-2-(1-imidazolyl)quinazoline,

[0127] 464-(2-(2-hydroxyethoxy)ethyl)amino-6-carboxy-2-(1-imidazolyl)quinazoline,

[0128] 474-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline,

[0129] 484-(2-(2-hydroxyethoxy)ethyl)amino-6-amino-2-(1-imidazolyl)quinazoline,

[0130] 494-(2-(2-hydroxyethoxy)ethyl)amino-6-(N,N-dimethylamino)-2-(1-imidazolyl)quinazoline,

[0131] 504-(2-(2-hydroxyethoxy)ethyl)amino-6-acetylamino-2-(1-imidazolyl)quinazoline

[0132] 514-(2-(2-hydroxyethoxy)ethyl)amino-6-methanesulfonylamino-2-(1-imidazolyl)quinazoline

[0133] 524-(2-(2-hydroxyethoxy)ethyl)amino-6-sulfamoyl-2-(1-imidazolyl)quinazoline,

[0134] 534-(2-(2-hydroxyethoxy)ethyl)amino-6-acetoxy-2-(1-imidazolyl)quinazoline,

[0135] 544-(2-(2-hydroxyethoxy)ethyl)amino-6-bromo-2-(1-imidazolyl)quinazoline,

[0136] 554-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline,

[0137] 564-(2-(2-hydroxyethoxy)ethyl)amino-7-fluoro-2-(1-imidazolyl)quinazoline,

[0138] 574-(2-(2-hydroxyethoxy)ethyl)amino-6-trifluoromethyl-2-(1-imidazolyl)quinazoline,

[0139] 584-(2-(2-hydroxyethoxy)ethyl)amino-6-hydroxy-2-(1-imidazolyl)quinazoline,

[0140] 594-(2-(2-hydroxyethoxy)ethyl)amino-6-nitro-2-(1-imidazolyl)quinazoline,

[0141] 604-(2-(2-hydroxyethoxy)ethyl)amino-6-cyano-2-(1-imidazolyl)quinazoline,

[0142] 61 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-azepinyl)quinazoline,

[0143] 624-(2-(2-hydroxyethoxy)ethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,

[0144] 634-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-pyrimidinyl)quinazoline,

[0145] 64 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-triazinyl)quinazoline,

[0146] 65 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-pyridyl)quinazoline,

[0147] 66 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(4-pyridyl)quinazoline,

[0148] 674-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,

[0149] 684-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,

[0150] 69 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-pyrrolyl)quinazoline,

[0151] 704-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-ethyl-1-imidazolyl)quinazoline,

[0152] 714-(2-(2-hydroxyethoxy)ethyl)amino-2-((1-imidazolyl)methyl)quinazoline,

[0153] 724-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,

[0154] 73 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-triazolyl)quinazoline,

[0155] 74 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-thienyl)quinazoline,

[0156] 75 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(2-furyl)quinazoline,

[0157] 764-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-azepinyl)quinazoline,

[0158] 774-(2-(2-hydroxyethylthio)ethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,

[0159] 784-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-pyrimidinyl)quinazoline,

[0160] 794-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-triazinyl)quinazoline,

[0161] 80 4-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-pyridyl)quinazoline,

[0162] 81 4-(2-(2-hydroxyethylthio)ethyl)amino-2-(4-pyridyl)quinazoline,

[0163] 824-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,

[0164] 834-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,

[0165] 844-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-pyrrolyl)quinazoline,

[0166] 854-(2-(2-hydroxyethylthio)ethyl)amino-2-(1-imidazolyl)quinazoline,

[0167] 864-(2-(2-hydroxyethylthio)ethyl)amino-2-((1-imidazolyl)methyl)quinazoline

[0168] 874-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,

[0169] 884-(2-(2-hydroxyethylthio)ethyl)amino-2-(1-triazolyl)quinazoline,

[0170] 89 4-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-thienyl)quinazoline,

[0171] 90 4-(2-(2-hydroxyethylthio)ethyl)amino-2-(2-furyl)quinazoline,

[0172] 914-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-((3-pyridyl)methyl)quinazoline,

[0173] 924-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-((3-pyridyl)methyl)quinazoline,

[0174] 934-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-((3-pyridyl)methyl)quinazoline,

[0175] 944-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-((3-pyridyl)methyl)quinazoline,

[0176] 954-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(2-(3-pyridyl)ethyl)quinazoline,

[0177] 964-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-(2-(3-pyridyl)ethyl)quinazoline,

[0178] 974-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-(2-(3-pyridyl)ethyl)quinazoline,

[0179] 984-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(2-(3-pyridyl)ethyl)quinazoline,

[0180] 994-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(2-(3-pyridyl)vinyl)quinazoline,

[0181] 1004-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-(2-(3-pyridyl)vinyl)quinazoline,

[0182] 1014-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-(2-(3-pyridyl)vinyl)quinazoline,

[0183] 1024-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(2-(3-pyridyl)vinyl)quinazoline,

[0184] 1034-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-((1-imidazolyl)methyl)quinazoline,

[0185] 1044-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-((1-imidazolyl)methyl)quinazoline,

[0186] 1054-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-((1-imidazolyl)methyl)quinazoline,

[0187] 1064-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-((1-imidazolyl)methyl)quinazoline,

[0188] 1074-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxy-2-(2-(1-imidazolyl)ethyl)quinazoline,

[0189] 1084-(2-(2-hydroxyethoxy)ethyl)amino-6-chloro-2-(2-(1-imidazolyl)ethyl)quinazoline,

[0190] 1094-(2-(2-hydroxyethoxy)ethyl)amino-6-ethynyl-2-(2-(1-imidazolyl)ethyl)quinazoline,

[0191] 1104-(2-(2-hydroxyethoxy)ethyl)amino-6-methoxycarbonyl-2-(2-(1-imidazolyl)ethyl)quinazoline,

[0192] 1114-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-azepinyl)quinazoline,

[0193] 1124-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,

[0194] 1134-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-pyrimidinyl)quinazoline,

[0195] 1144-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-triazinyl)quinazoline,

[0196] 1154-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-pyridyl)quinazoline,

[0197] 1164-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(4-pyridyl)quinazoline,

[0198] 1174-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,

[0199] 1184-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,

[0200] 1194-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-pyrrolyl)quinazoline,

[0201] 1204-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(1-imidazolyl)quinazoline,

[0202] 1214-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-((1-imidazolyl)methyl)quinazoline,

[0203] 1224-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,

[0204] 1234-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(1-triazolyl)quinazoline,

[0205] 1244-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-thienyl)quinazoline,

[0206] 1254-(2-(2-hydroxyethylsulfinyl)ethyl)amino-2-(2-furyl)quinazoline,

[0207] 1264-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-azepinyl)quinazoline,

[0208] 1274-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(1,5-diazepin-2-yl)quinazoline,

[0209] 1284-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-pyrimidinyl)quinazoline,

[0210] 1294-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-triazinyl)quinazoline,

[0211] 1304-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-pyridyl)quinazoline,

[0212] 1314-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(4-pyridyl)quinazoline,

[0213] 1324-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-(3-pyridyl)ethyl)quinazoline,

[0214] 1334-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-(3-pyridyl)vinyl)quinazoline,

[0215] 1344-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-pyrrolyl)quinazoline,

[0216] 1354-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(1-imidazolyl)quinazoline,

[0217] 1364-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-((1-imidazolyl)methyl)quinazoline,

[0218] 1374-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-methyl-1-imidazolyl)quinazoline,

[0219] 1384-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(1-triazolyl)quinazoline,

[0220] 1394-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-thienyl)quinazoline,

[0221] 1404-(2-(2-hydroxyethylsulfonyl)ethyl)amino-2-(2-furyl)quinazoline,

[0222] and further those described in Examples below are alsorepresentative compounds of the present invention.

[0223] The compounds of Formula (I), if desired, may be converted intoacid addition salts by known methods. Preferably, acid addition saltsare non-toxic and water-soluble. The suitable acid addition salts are,for example, salts of an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid,nitric acid, or an organic acid such as acetic acid, lactic acid,tartaric acid, benzoic acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,isethionic acid, glucuronic acid and gluconic acid.

[0224] The compounds of Formula (I), if desired, may be converted intosalts by known methods. Preferable, salts are non-toxic salts andwater-soluble. The suitable salts are salts of alkaline metal (sodium,potassium etc.), salts of alkaline earth metal (calcium, magnesiumetc.), ammonium salts, salts of pharmaceutically acceptable organicamine (tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, phenylmethylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine etc.).

[0225] Throughout the specification including claims, it may be easilyunderstood by those skilled in the art, that the alkyl, alkoxy, groupsinclude straight-chained and also branched-chained ones. Accordingly,all isomers produced by any differences in stereo configuration, such asasymmetric carbons are included in the present invention.

[0226] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person are generally between .06 mg and 3.7 mg byoral or parenteral administration, up to several times per day, orcontinuous administration between 1 and 24 hrs. per day intravenously.

[0227] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases in which doses lower than orgreater than the ranges specified above may be used.

[0228] The following examples from the above U.S. patent are intended toillustrate, but not limit, compounds useful in practicing the methods ofthe present invention.

EXAMPLE 1 4-Fluoroisatoic Anhydride

[0229] To a solution of 2-amino-4-fluorobenzoic acid (4.65 g) in 50 mlof mixed solvent (10:1=toluene:tetrahydrofuran) is added phosgene (4.46g, 1.93M solution of toluene ) dropwise via a drop funnel. The mixtureis stirred at room temperature for 1 hour and then heated to refluxovernight. The mixture is concentrated to about 10 ml and cooled inrefrigerator. The precipitate is filtered, washed with ether (5 ml×2)and air-dried to give the title compound (5.43 g) as a white solidhaving the following physical data.

[0230] NMR (200 MHz, DMSO-d6): delta 6.92 (dd, 1H), 7.11 (td, 1H), 8.00(dd, 1H), 11.92 (broad, 1H).

EXAMPLE 2 4-Fluoroanthranilamide

[0231] A solution of the isatoic anhydride compound (3.62 g, prepared inExample 1) in 100 ml of tetrahydrofuran is placed in a 200 ml roundbottle equipped with gas in- and outlet. The anhydrous ammonia gas isgently bubbled into the solution for 1.5 to 2 hours. After removal ofthe solvent the residue is taken up in methylene chloride (30 ml) andwater (30 ml). The precipitate is collected by filtration and washedwith methylene chloride (10 ml) to give the title compound (1.95 g) as apale white solid having the following physical data.

[0232] NMR (200 MHz, DMSO-d6): delta 6.70 (m, 1H), 6.82 (m, 1H), 6.90(broad, 2H), 7.72 (m, 1H).

[0233] The following compounds are obtained by the same procedure asExample 1 and Example 2, by using the corresponding substitutedanthranilic acid compound.

EXAMPLE 2(a) 5-Methylanthranilamide

[0234] The product is collected by filtration as a pale solid.

[0235] NMR (200 MHz, DMSO-d6): delta 2.24 (s, 3H), 5.50 (broad, 2H),6.62 (d, 1H), 7.07 (dd, 1H), 7.16 (d, 1H).

EXAMPLE 2(b) 5-Chloroanthranilamide

[0236] The product is collected by filtration as a pale solid.

[0237] NMR (200 MHz, DMSO-d6): delta 5.68 (broad, 2H), 6.64 (d, 1H),7.20 (dd, 1H), 7.35 (d, 1H).

EXAMPLE 2(c) 5-Bromoanthranilamide

[0238] The product is collected by filtration as a pale brown.

[0239] NMR (200 MHz, DMSO-d6): delta 6.66 (dd,1 H), 6.72 (broad, 2H),7.20 (broad, 1H), 7.26 (dt, 1H), 7.70 (t, 1H), 7.82 (broad, 1H).

EXAMPLE 2(d) 5-Nitroanthranilamide

[0240] The product is collected by filtration as a solid.

[0241] NMR (200 MHz, DMSO-d6): delta 6.80 (dd,1 H), 7.40 (broad, 1H),7.90 (broad, 2H), 8.03 (dt, 1H), 8.20 (broad, 1H), 8.56 (t, 1H).

EXAMPLE 3 4-Fluoro-2-[N-(3-Pyridylcarbonyl)Amino]Benzamide

[0242] To a solution of the anthranilamide compound (1.54 g, prepared inExample 2) and triethylamine (1.4 g) in 100 ml of tetrahydrofuran isadded nicotinoyl chloride hydrochloride (1.95 g). The resulting mixtureis heated to reflux for one to three days and then concentrated. Theresidue is taken up in water (25 ml) and chloroform (30 ml). Theinsoluble crude product is collected by filtration and then vacuumdried. The crude product is triturated with 10 ml of ether and pentanesolution (1:1) to afford the title compound (2.27 g) as a white solidhaving the following physical data.

[0243] NMR (200 MHz, DMSO-d6): delta 7.10 (td, 1H), 7.80 (m, 1H), 7.99(broad, 1H), 8.07 (m, 1H), 8.40-8.55 (m, 3H), 8.90 (m, 1H), 9.15 (m,1H).

EXAMPLE 4 7-Fluoro-2-(3 -Pyridyl)Quinazoiln-4-One

[0244] To a suspension of the benzamide compound (1.6 g, prepared inExample 3) in 60 ml of toluene is added sodium methoxide (853 mg). Thesolution is heated to reflux for one to three days. After cooling toroom temperature, the mixture is quenched with ammonium chloridesolution (30 ml) with a vigorously shaking. The mixture is cooled inrefrigerator and the insoluble product is collected by filtration anddried in vacuum to give the title compound (1.39 g) as a white solidhaving the following physical data.

[0245] NMR (200 MHz, DMSO-d6): delta 7.43 (td, 1H), 7.53-7.64 (m, 2H),8.20-8.28 (m, 1H), 8.50 (dt, 1H), 8.78 (dd, 1H), 9.29 (m, 1H).

EXAMPLE 5 4-Chloro-7-Fluoro-2-(3-Pyridyl)Quinazoline Hydrochloride

[0246] A suspension of the quinazolinone compound (1.2 g, prepared inExample 4) in 20 ml of thionyl chloride is heated to reflux for threehours. The excess of thionyl chloride is removed by distillation. Theresidue is distilled azeotropically with benzene (5 ml×3) and thenreduced the total volume to about 5 ml. After cooling in refrigerator,precipitate is collected by filtration and washed with benzene twice togive the title compound (1.38 g) as a crystalline solid having thefollowing physical data.

[0247] NMR (200 MHz, DMSO-d6): delta 7.80-7.95 (m, 2H), 8.07 (dd, 1H),8.43-8.49 (m, 1H), 8.95 (d, 1H), 9.06 (dr, 1H), 9.65 (m, 1H).

[0248] The following compounds are obtained by the same procedure asExample 3 arrow right Example 4 arrow right Example 5, by using theanthranilamide compound prepared in Examples 2(a), 2(b) or 2(c), orbeing on sale, and the corresponding acid chloride.

EXAMPLE 5(a) 4-Chloro-6-Methyl-2-(3-Pyridyl)Quinazoline Hydrochloride

[0249] The product is collected by filtration as a white solid.

[0250] NMR (200 MHz, DMSO-d6): delta 2.62 (s, 3H), 7.96-8.14 (m, 4H),8.98 (d, 1H), 9.16 (d, 1H), 9.63 (m, 1H).

EXAMPLE 5(b) 4,6-Dichloro-2-(3-Pyridyl)Quinazoline Hydrochloride

[0251] The product is collected by filtration as a white solid.

[0252] mp: 210°-214° C.

[0253] NMR (CDC13): delta 7.28-8.17 (m, 3H), 8.35 (m, 1H), 8.89 (dd,1H), 9.55 (dt, 1H), 9.98 (d, 1H).

EXAMPLE 5(c) 4-Chloro-6,7-Dimethoxy-2-(3-Pyridyl)QuinazolineHydrochloride

[0254] The product is collected by filtration as a white solid.

[0255] NMR (200 MHz, DMSO-d6): delta 4.04 (s, 3H), 4.06 (s, 3H), 7.46(s, 1H), 7.56 (s, 1H), 7.95 (m, 1H), 8.93 (d, 1H), 9.09 (d, 1H), 9.60(m, 1H).

EXAMPLE 5(d) 4-Chloro-2-(2-Pyridyl)Quinazoline

[0256] The product is collected by filtration as a light brown powder.

[0257] mp: 120°-121° C.

EXAMPLE 5(e) 6-bromo-4-Chloro-2-(3-Pyridyl)quinazoline Hydrochloride

[0258] NMR (200 MHz, DMSO-d6): delta 8.02 (m, 1H), 8.14 (dd, 1H), 8.33(dt, 1H), 8.50 (t, 1H), 9,01 (d, 1H), 9.14(d, 1H), 9.64 (t, 1H).

EXAMPLE 6 2-[N-(3-pyridylcarbonyl)amino]benzamide

[0259] To a solution of anthranilamide (8.2 g, being on sale) andtriethylamine (18.0 g)in 100 ml of tetrahydrofuran/methylene chloride(1:1), is added nicotinoyl chloride hydrochloride (10.8 g). The mixtureis allowed to stir at room temperature, under nitrogen atmosphere, forsix hours. The solution is then concentrated under reduced pressure. Theconcentrate is taken up in ethyl acetate and water and the mixturefiltered. The solid material is triturated in ether and filtered to givethe title compound (11.5 g) as a yellow powder having the followingphysical data.

[0260] mp: 220°-222° C.

EXAMPLE 7 2-(3 -Pyridyl)Quinazolin-4-One

[0261] To a solution of the benzamide compound (11.5 g, prepared inReference example 6) in 100 ml of toluene is added 95% sodium methoxide(5.7 g). The solution is heated at 60°-80° C. for three hours undernitrogen atmosphere. After cooling to room temperature, the solution isdiluted with ammonium chloride solution. After stirring for one-halfhour, the mixture is filtered. An NMR of the filtered material indicatedthe reaction is incomplete. The material is taken up in toluene andethanol and 95% sodium methoxide (5.7 g) is added. The resultingsolution is heated to reflux and stirred via a mechanical stirrer, undernitrogen atmosphere, overnight. The solvent is thereby evaporated, andthe concentrate in the flask is collected and washed with ammoniumchloride solution and methylene chloride. The solid material iscollected by filtration and allowed to dry to give the title compound asa gray powder having the following physical data.

[0262] mp: 275°-276° C.

[0263] NMR (200 MHz, DMSO-d6): delta 7.50-7.61 (m, 2H), 7.75-7.90 (m,2), 8.16 (d, 1H), 8.49 (m, 1H), 8.77 (d, 1H), 9.31 (s, 1H).

[0264] IR (KBr): nu 3185 (w), 3045 (m), 2915 (w), 1677 (s), 1603 (m),1558 (w), 1474 (m), 769 (m)cm⁻¹.

EXAMPLE 8 4-Chloro-2-(3-Pyridyl)Quinazoline

[0265] A solution of the quinazolinone compound (6.7 g, prepared inReference example 7) and 5.7 ml of N,N-dimethylaniline in 200 ml ofbenzene is heated to reflux, under nitrogen atmosphere, for one-halfhour with the removal of 15 ml of distillate. After cooling to roomtemperature, phosphorus oxychloride (4.5 g) is added and the resultingsolution heated to reflux for six hours. After cooling to roomtemperature, the solution is washed with ice water and dilute sodiumhydroxide solution. The organic extract Is dried over sodium sulfate andconcentrated under reduced pressure. The concentrate is triturated inether and collected to give the title compound (3.0 g) (mp: 178°-179°C.).

[0266] The following compounds are obtained by the same procedure asExample 6 arrow right Reference example 7 arrow right Example 8, byusing anthranilamide and the corresponding acid chloride.

EXAMPLE 8(a) 4-Chloro-2-(4-Pyridyl)Quinazoline

[0267] The product is collected by filtration as a brown solid.

[0268] mp: 158°-160° C.

EXAMPLE 8(b) 4-Chloro-2-(2-Chloro-5-Pyridyl)Quinazoline

[0269] NMR (CDC13): delta 7.47 (d, 1H), 7.73 (t, 1H), 7.95 (t, 1H),8.05-8.32 (m, 2H), 8.81 (dd, 1H), 9.55 (ds, 1H).

EXAMPLE 8(c) 4-Chloro-2-(2-Thienyl)Quinazoline

[0270] The product is collected by filtration as a tan powder.

[0271] mp: 121°-124° C.

EXAMPLE 8(d) 4-Chloro-2-(2-Furyl)Quinazoline

[0272] The product is collected by the filtration as a tan powder.

[0273] mp: 116°-119° C.

EXAMPLE 9 5-Nitro-2-[N-(3-Pyridylcarbonyl)Amino]Benzamide

[0274] The title compound is obtained by the same procedure as Referenceexample 3, by using 5-nitroanthranilamide (prepared in Example 2 (d)).

[0275] The product is collected by filtration as a white solid.

[0276] NMR (200 MHz, DMSO-d6): delta 7.70 (m, 1H), 8.20 (broad, 1H),8.35 (dt, 1H), 8.49 (dd, 1H), 8.85-8.92 (m, 3H), 9.15 (t, 1H).

EXAMPLE 10 4-Chloro-6-Nitro-2-(3-Pyridyl)Quinazoline

[0277] A suspension of the benzamide compound (0.925 g, prepared inReference example 9) in phosphorous oxychloride (6 ml) is heated toreflux for 16 hours. After cooling to room temperature, the mixture isdiluted by chloroform (30 ml) and then poured into 30 ml of ice-watermixture. The mixture is cooled in ice bath and carefully neutralized topH 8 with a temperature control under 10o C. The aqueous layer isextracted with chloroform (50 ml×3). Combined organic layers are driedover with potassium carbonate and concentrated under reduced pressure togive the title compound (0.8 g) having the following physical data.

[0278] NMR (CDCl₃): delta 7.27-7.35 (m, 2H), 7.52 (dd, 1 Hi, 8.46-8.63(m, 3Hi, 8.87 (d, 1H), 9.42 (s, 1H).

EXAMPLE 11 4-Phenylmethylamino-7-Fluoro-2-(3-Pyridyl)Quinazoline

[0279] To a warm solution of the 4-chloroquinazoline compound (1.18 g,prepared in Reference example 5) in 50 ml ethanol is addedphenylmethylamine (2.00 g). The mixture is heated to reflux for sixteenhours. The solution is then concentrated, and the residue taken up inchloroform and ammonium chloride solution. The aqueous layer isextracted with chloroform (30 ml×3) and dried over sodium sulfate. Afterconcentration, the residue is triturated in pentane/ether solution togive the title compound (0.88 g) as a pale white solid having thefollowing physical data.

[0280] mp: 199°-203° C.

[0281] NMR (CDCl₃): delta 5.00 (d, 2H), 6.01 (broad, 1H), 7.20 (td, 1H),7.25-7.50 (m, 6H), 7.55 (dd, 1H), 7.70-7.77 (m, 1H), 8.70 (dd, 1H), 8.79(dt, 1H), 9.74 (m, 1H).

[0282] IR (KBr): nu 697 (s), 775 (s), 1166 (m), 1259 (m), 1341 (s), 1375(s), 1444 (s), 1535 (s), 1592 (s), 1626 (s), 3135 (m), 3250 (m) cm⁻¹.

EXAMPLE 12 4-Phenylmethylamino-7-Fluoro-2-(3-Pyridyl)QuinazolineDihydrochloride

[0283] To a suspension of the free base (0.70 g, prepared in Example 11)in 10 ml methanol is added excess amount of HCl in methanol. The mixtureis stirred at room temperature for one-half hour. The solvent isremoved, and the residue is triturated in ether (30 ml). The titlecompound (0.84 g) as a white powder having the following physical data,is obtained after filtration.

[0284] mp: 250° C.

[0285] NMR (CDCl3): delta 4.50 (d, 2H), 7.25-7.40 (m, 3H), 7.49-7.53 (m,2H), 7.64 (dt, 1H), 7.82 (dd, 1H), 7.99 (m, 1H), 8.67 (m, 1H), 8.97 (dd,1H), 9.15 (dd, 1H), 9.60 (d, 1H), 10.18 (broad, 1H).

[0286] IR (KBr): nu 704 (m), 1266 (m), 1457 (s), 1574 (s), 1632 (s),2920-2440 (broad, s), 3115 (broad, s) cm⁻¹.

EXAMPLE 13

[0287] The following compounds are obtained by the same procedure asExample 11, or Example 11 and Example 12, by using the corresponding4-chloroquinazoline compound prepared by Examples 5, 5(a) to 5(e) orExample 8, 8(a) to 8(d) and the proper amine.

[0288] 4-Phenylmethylamino-6-Methyl-2-(3-Pyridyl)Quinazoline And ItsSalt

[0289] 4-Phenylmethylamino-6-Chloro-2-(3-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0290] 4-Phenylmethylamino-6,7-Dimethoxy-2-(3-Pyridyl)Quinazoline AndIts Dihydrochloride Salt

[0291] 4-Phenylmethylamino-2-(2-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0292] 4-Phenylmethylamino-2-(3-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0293] 4-Phenylamino-2-(3 -Pyridyl)Quinazoline

[0294] 4-(3-Methoxycarbonylphenyl)Amino-2-(3 -Pyridyl)Quinazoline

[0295] 4-(4-Carboxyphenylmethyl)Amino-2-(3-Pyridyl)Quinazoline

[0296] 4-(2-Thienylmethyl)Amino-2-(3-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0297] 4-(3-Chlorophenylmethyl)Amino-2-(3-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0298] 4-(3-Pyridylmethyl)Amino-2-(3-Pyridyl)Quinazoline And Its Salt

[0299] 4-(3,4-Dimethoxyphenylmethyl)Amino-2-(3-Pyridyl)Quinazoline AndIts Dihydrochloride Salt

[0300] 4-Phenylethylamino-2-(3-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0301] 4-(3-Trifiuoromethylphenylmethyl) Amino-2-(3-Pyridyl)QuinazolineDihydrochloride

[0302] 4-(4-N,N-Dimethylamino)PhenylmethylAmino-2-(3-Pyridyl)QuinazolineTrihydrochloride

[0303] 4-(4-Sulfamoylphenylmethyl)Amino-2-(3-Pyridyl)QuinazolineDihydrochloride

[0304] 4-Phenytmethylamino-2-(4-Pyridyl)Quinazoline And ItsDihydrochloride Salt

[0305] 4-Phenylamino-2-(4-Pyridyl)Quinazoline

[0306] 4-Phenylmethylamino-2-(2-Chloro-5-Pyridyl)Quinazoline

[0307] 4-Phenylmethylamino-2-(2-Thienyl)Quinazoline

[0308] 4-Phenylamino-2-(2-Thienyl)Quinazoline

[0309] 4-Phenylmethylamino-2-(2-Furyl)Quinazoline

[0310] 4-Phenylamino-2-(2-Furyl)Quinazoline

[0311]6-Chloro-4-(2-(1-Methyl-2-Pyrrolyl)Ethyl)Amino-2-(3-Pyridyl)QuinazolineAnd Its Dihydrochloride Salt

[0312] 4-Phenylmethylamino-6-Bromo-2-(3-Pyridyl) Quinazoline And ItsDihydrochloride Salt

[0313] 4-Phenylmethylamino-6-Nitro-2-(3-Pyridyl) Quinazoline And ItsDihydrochloride Salt

[0314] 4-(Cyclopropylmethyl)Amino-2-(3-Pyridyl) Quinazoline And ItsDihydrochloride Salt

[0315] 4-(3-Methylphenylmethyl)Amino-2-(3-Pyridyl)

[0316] 4-(2-(1-Methyl-2-Pyrrolyl)Ethyl)Amino-2-(3-Pyridyl)Quinazoline

[0317] 4-(3-Nitrophenylmethyl)Amino-2-(3-Pyridyl) Quinazoline And ItsDihydrochloride Salt

[0318] 4-(5-Methyl-3-Isoxazolyl)Amino-2-(3-Pyridyl) Quinazoline And ItsDihydrochloride Salt

[0319] The following compounds are obtained by the same procedure asdescribed in Examples 2, 3, 4 and 5 and Examples 11 and 12 or in Example6, 7 and 8 and Examples 11 and 12, by using isatoic anhydride.

[0320] 6-Iodo-4-Phenylmethylamino-2-(3-Pyridyl)QuinazolineDihydrochloride

[0321] 6-Fluoro-4-Phenylmethylamino-2-(3-Pyridyl)QuinazolineDihydrochloride

[0322] 4-(3-Carboxyphenyl)Amino-2-(4-Pyridyl)Quinazoline

EXAMPLE 14 6-Acetylamino-4-Phenylmethylamino-2-(3-Pyridyl)Quinazoline

[0323] To warmed suspension of the nitroquinazoline compound (141 mg,prepared in Example 13(z)) in acetic acid (4 ml) is added zinc dust (80mg). The red mixture is heated to reflux for overnight. After coolingdown to room temperature, the precipitate is removed by filtration. Thefiltrate is neutralized to pH 8 and extracted with chloroform. Theinsoluble solid is removed by filtration during the extraction. Thechloroform is dried over potassium carbonate and then concentrated to0.5 ml (total volume). The precipitate is collected by filtration togive the title compound (20 mg).

EXAMPLE 15 6-Chloro-(1h,3h)-Quinazolin-2,4-Dione

[0324] To a solution of 5-chloroanthranilamide (3.4 g) intetrahydrofuran (50 ml) is added phosgene (16 ml, 1.93M solution intoluene) via an addition funnel. The reaction mixture is stirred at roomtemperature for 4 hours and then heated to reflux for another two hours.The reaction mixture is concentrated to a total volume about 10 ml.After cooling, the title compound (3.72 g) having the following physicaldata is collected by filtration and dried in vacuum.

EXAMPLE 16 4-Chloro-2-Chloromethvlquinazoline

[0325] To a solution of anthranilonitrile (11.8 g) andchloroacetonitrile (7.5 g) in 1,4-dioxane (200 ml), cooled in an icebath, is bubbled HCl gas. The reaction mixture is stirred for two andone-half hours at which time the reaction is allowed to warm to roomtemperature and continued to bubble HCl gas for 16 hours. After the HClgas bubbling is ceased, nitrogen gas is bubbled through to remove anyunreacted HCl gas. The mixture is concentrated at 45o C. in vacuo. Themixture is partitioned between methylene chloride (300 ml) and water(400 ml). The organic layer is separated, dried over anhydrous magnesiumsulfate, and concentrated. The concentrate is dissolved in 200 ml ofwarm hexane, filtered and allowed to cool to room temperature. The titlecompound (9.1 g) is collected by filtration.

EXAMPLE 17 2,4-Dichloroquinazoline

[0326] A mixture of benzoyleneurea (20.0 g), phosphorus oxychloride (100ml) and N,N-dimethylaniline (12 ml) is,refluxed for five hours. Afterstirring overnight at room temperature, the mixture is heated to refluxonce more for an additional four hours. The cooled mixture is thenpoured into ice and the precipitate collected. The precipitate ispurified on silica gel column with 5% methanol/chloroform as eluent. Theisolated product is triturated in ether/hexane and collected to obtainthe title compound (6.9 g).

[0327] The following compound is obtained by the same procedure asExample 17, by using 6-chloro-(1H,3H)-quinazolin-2,4-dione prepared byExample 15: 2,4,6-Trichloroquinazoline.

EXAMPLE 18 4-Phenylmethylamino-2-Chloroquinazoline

[0328] The title compound is obtained by the same procedure as Example11, by using the dichloroquinazoline prepared in Example 17 andphenylmethylamine (equivalent to dichloroquinazoline).

EXAMPLE 19 4-Phenylmethylamino-2-(1-Imidazolyl)Quinazoline

[0329] A mixture of the 4-phenylmethylamino-2-chloroquinazoline (0.81 g,prepared in Example 18), imidazole (0.81 g) and phenol (3.0 g) is heatedto reflux for four and one-half hours. The mixture is then taken up inchloroform, washed twice with sodium hydroxide solution, dried overanhydrous potassium carbonate and concentrated. The concentrate istriturated in ether and collected to obtain the title compound (0.7 g)as a yellow solid.

[0330] The following compounds are obtained by the same procedure asExample 19, by using 4-phenylmethylamino-2-quinazoline prepared inExample 18 or corresponding quinazoline, and the proper heterocycliccompounds:

[0331] 4-phenylmethylamino-2-(2-methyl-1-imidazolyl )quinazoline,

[0332] 4-phenylmethylamino-2-( 1,2,4-triazol-1-yl)quinazoline,

[0333] 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazoline,

[0334] 4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazoline, and

[0335] 6-ethoxycarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline

EXAMPLE 20 4-Phenylmethylamino-2-(1-Imidazolyl)QuinazolineDihydrochloride

[0336] The title compound is obtained by the same procedure as Example12, by using the free base prepared in Example 19 and HCl/methanolsolution.

[0337] By the same procedure as described in Example 17 and 18 andExample 19 and 20, the following compounds can be made:

[0338] 4-phenylmethylamino-6-chloro-2-(1-imidazolyl)quinazolinedihydrochloride,

[0339] 4-phenylmethylamino-2-((1-imidazolyl)methyl)quinazolinedihydrochloride.

[0340] The following compounds are obtained by the same procedure asdescribed in Examples 17, 18 and Examples 19 and 20, by using thecorresponding (1H,3H)-quinazoline-2,4-dione or its derivative andcorresponding amine:

[0341] 6-bromo-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0342] 7-chloro-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,

[0343] 6-chloro-4-phenylmethylamino-2-(1-imidazolylmethyl)quinazoline,

[0344] 6-nitro-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride,

[0345] 6-methoxy-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0346] 6-chloro-4-phenylamino-2-(1-imidazolylmethyl)quinazolinedihydrochloride,

[0347]6-chloro-4-(3-carboxyphenyl)amino-2-(1-imidazolylmethyl)quinazolinedihydrochloride,

[0348]6-dimethylaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride,

[0349] 4-(2-furylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0350] 4-(2-thienylmethyl)amino-2-(1-imidazolyl)quinazoline,

[0351] 4-(2-tetrahydrofuranylmethyl)amino-2-(1-imidazolyl)quinazoline,

[0352] 4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0353]4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydro-quinazolinedihydrochloride,

[0354]6-dimethylaminomethylideneaminosulfonyl-4-phenylmethylamino-2-(1imidazolyl)quinazolinedihydrochloride,

[0355]6-(phenylmethylaminosulfonyl)-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,

[0356] 4-(2-phenylethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0357] 4-cyclohexyl methylamino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0358]6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazoline

[0359]6-phenylmethylaminocarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0360] 4-(4-tetrahdyropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0361]6-methoxy-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0362]6-chloro-4-(4-tetrahydropyranylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0363] 6-iodo-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0364]4-(4-trifuloromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0365] 4-(3-trifluoromethoxyphenylmethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0366]6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride,

[0367]4-(2-methoxyethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolinedihydrochloride,

[0368] 4-(2-methoxyethyl)amino-6-iodo-2-(1-imidazolyl)quinazolinedihydrochloride,

[0369] 4-phenylmethylamino-6,8-diiodo-2-(1-imidazolyl)quinazolinedihydrochloride,,

[0370]4-(2-methoxyethyl)amino-6-methoxy-2-(2-methyl-1-imidazolyl)quinazolinedihydrochloride,

[0371] 4-(2-hydroxyethyl)amino-6-methoxy-2-(1-imidazolyl)quinazolinedihydrochloride,

[0372] 4-(2-methoxyethyl)amino-6,8-diiodo-2-(1-i midazolyl)quinazolinedihydrochloride,

[0373] 4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazoline dihydrochloride,

[0374] 4-(2-phenoxyethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline andits dihydrochloride,

[0375]4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline andits dihydrochloride,

[0376] 4-(2-methoxyethyl)amino-6-methylthio-2-(1-imidazolyl)quinazolineand its dihydrochloride salt,

[0377]4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline,

[0378]4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazolinedihydrochloride,

[0379] 6-.methylthio-4-phenylmethylamino-2-(1imidazolyl)quinazolinedihydrochloride,

[0380] 4-(3-methoxypropyl)amino-6-methoxy-2-(1imidazolyl) quinazolinedihydrochloride,

[0381] 4-(2-methoxyethyl)amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline,

[0382] 4-[2-(2-hydroxyethoxy)ethyl]amino-6-methoxycarbonyl-2-(1-imidazolyl) quinazoline,

[0383] 4-(2-methylthioethyl)amino-6-methoxyo-2-1-imidazolyl)quinazoline,

[0384]4-(2-methylsulfinylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,

[0385]4-(2-methylsulfonylethyl)amino-6-methoxy-2-(1-imidazolyl)quinazoline.

EXAMPLE 21 2-(2-(3-Pyridyl)Vinyl)Quinazolin-4-One

[0386] A mixture of 2-methylquinazolin-4-one (6.1 g) and3-pyridinecarbaldehyde (4.1 g) in acetic acid (80 ml) is heated toreflux for 20 hours. After cooling to room temperature, the precipitateis collected by filtration, ished with methanol and dried to obtain thetitle compound as an acetic acid salt (10.5 g).

EXAMPLE 22 4-Chloro-2-(2-(3-Pyridyl)Vinyl)Quinazoline

[0387] A suspension of the quinazolinone compound (2.9 g, prepared inExample 21) in thionyl chloride (25 ml) and a few drops ofdimethylformamide is heated at reflux for three hours. The mixture isthen concentrated, the concentrate poured into 150 ml portions ofchloroform, dried over potassium carbonate and concentrated to obtainthe title compound (1.1 g) as a red oil.

EXAMPLE 23 4-Phenylmethylamino-2-(2-(3-Pyridyl)Vinyl)Quinazoline

[0388] The title compound is obtained by the same procedure as Example11, by using the 4-chloro compound prepared in Example 22 andphenylmethylamine. The product is purified by column chromatography.

[0389] mp: 178°-179° C.

[0390] NMR(CDCl3): delta 4.96 (d, 2H), 6.11 (broad, 1H), 7.30-7.55 .(m,8H), 7.70-7.81 (m, 2H), 7.99 (d, 1H), 8.34 (s, 1H), 8.36-e.45 (m, 1H),8.55-8.5e (dd, 1H), 8.9-8.91 (d, 1H).

[0391] IR (KBr): nu 3300 (m), 1577 (s), 1528 (s), 1434 (m), 1378 (s),763 (m), 699 (m) cm₁.

EXAMPLE 24 6-Ethoxycarbonyl-4-Phenylmethylamino-2-(1 -Imidazolyl)-5 6,7,8-Tetrahydroquinazoline

[0392] To 349 mg (1.0 mmol) of 4-phemylmethylamino-2-(1-imidazolyl)quinazoline dihydrochloride prepared in Example 20 dissolved in 20 ml oftetrahydrofuran is added 0.4 ml of thionyl chloride. Initially, a whiteprecipitate formed, but gradually all dissolved. After stirring for 15minutes, 20 ml of ethanol is added. After stirring an additional 15minutes, the mixture is concentrated, the concentrate triturated inether and collected. The solid is found to be very hygroscopic, is takenup in chloroform, treated with potassium carbonate solution, separated,dried over anhydrous magnesium sulfate and concentrated. 278 mg (0.7mmol, 73% yield) of the desired product is obtained as a white solid(free base).

[0393] mp: 196°-198° C.

[0394] NMR (DMSO- d6 ): delta 1.30 (t, 3H), 1.90 (m, 1H), 2.28 (m, 1H),2.60 (m, 2H), 2.82 (m, 3H), 4,23 (q, 2H), 4.77 (d, 2H), 5.12 (m, 1H),7.10 (s, 1H), 7.37 (m, 5H), 7.83 (s, 1H), 8.54 (s, 1H).

[0395] IR (KBr): 3245 (w), 1725 (ms), 1605 (s), 1532 (w), 1473 (m), 1426(m), 1333 (w) cm⁻¹.

[0396] To obtain the dihydrochloride salt of the title compound, asuspension of 240 mg (0.64 mmol) of the compound prepared above in 5 mlof ethanol is added 2 ml of approximately equal to 10% HCl in methanol.All the material gradually dissolved. After ten minutes, the mixture isconcentrated in vacuo, triturated in ether and filtered to obtain 229 mg(0.51 mmol) of the desired product. (2HCl salt)

[0397] mp: 158°-161° C.

[0398] N (200 MHz, DMSO-d6) delta: 1.22 (t, 3H), 1.87(m, 1H), 2.14 (m,1H), 2.55-3.00 (m, 5H), 7.79 (s, 1H), 8.23 (s, 1H), 9.77 (s, 1H).

[0399] IR (KBr) nu: 3225, 1718, 1642, 1612, 1518, 1393 cm⁻¹.

EXAMPLE 25 6-Ethylaminocarbonyl-4-Phenylmethylamino-2-(1-Imidazolyl)-5,6,7,8-Tetrahydroquinazoline Dihydrochloride

[0400] By the same procedure as described in Example 24, by usingethylamine instead of ethanol, the title compound having the followingphysical data is given.

[0401] mp: 147° C., (dec.)

[0402] NMR (200 MHz, DMSO-d6) delta: 1.04 (q, 3H), 1.65-2.06 (m, 2H),2.50-2.80 (m, 5H), 3.10 (m, 2H), 4.72 (m, 2H), 7.18-7.48 (m, 5H), 7.81(s, 1H), 8.05 (t, 1H), 8.18 (M, 1H), 8.24 (m, 1H), 9.82 (s, 1H).

[0403] IR (K-Br) nu: 3265-2580, 2365, 1653, 1613, 1576, 1540, 1449,1390, 1352, 1144, 1060, 750, 701,624 cm⁻¹.

EXAMPLE 26 4-Phenylmethylamino-2-(1-Imidazolyl)QuinazolineDimethanesulfonate

[0404] By the same procedure as described in Examples 17 and 18 andExample 19 and 20, by using methanesulfonic acid instead of hydrochloricacid, the title compound and the following compounds are given.

[0405] 6,7-dimethoxy-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedimethanesulfonate,

[0406] 4-(3,4-dimethoxyphenyl methyl)amino-2-(1-imidazolyl)quinazoline1.5 methanesulfonate, and4-(2-phenoxyethyl)amino-2-(1-imidazolyl)quinazoline dimethanesulfonate.

EXAMPLE 276-Carboxy-4-Phenylmethylamino-2-(1-Imidazolyl)-5,6,7,8-TetrahydroquinazolineSodium Salt

[0407] A solution of 200 mg (0.57 mmol) of6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinolazinedihydrochloride prepared in Example 20 dissolved in 25 ml oftetrahydrofuran is filtered to remove dark insoluble material present.To the filtrate is added 0.25 ml (0.62 mmol) of 2.5N sodium hydroxidesolution. Some precipitate formed. The mixture is concentrated andpumped in vacuum. The concentrate is triturated in tetrahydrofuran andether and filtered. The solid is washed with ether and filtered toobtain 190 mg (0.51 mmol) of the desired product as a white solid. mp:240o C., (dec.) NMR (200 MHz, DMSO-d6) delta: 1.50-1.82 (m, 2H),1.88-2.35 (m, 2H), 2.59 (m, 3H), 4.62 (s, 2H), 6.98 (s, 1H), 7.12-7.48(m, 5H), 7.73 (s, 1H), 7.86 (m, 1H), 8.33 (s, 1H).

[0408] By the same procedure as described in Example 27,6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)quinazoline sodium saltcan also be obtained.

EXAMPLE 28 4-(11-Dimethyl-2-Methoxyethyl)Amino-2-Chloroquinazoline

[0409] A mixture of 2,4-dichloroquinazoline (995 mg, 5 mmol),triethylamine (0.7 ml, 5 mmol) and 1,1-dimethyl-2-methoxyethylamine (30ml, 0.5M methanol sol., 15 mmol) is stood at room temperature for 1week. The reaction mixture is concentrated and partitioned between ethylacetate and water. The organic layer is washed with water and brine,dried over MgSO₄ and concentrated. The residue is purified on 50 g ofsilica gel column eluting with 50% ethyl acetate in hexane to obtain thetitle compound (176 mg) as a white solid.

[0410] NMR (CDCl₃): delta 1.60 (s, 6H), 3.46 (s, 3H), 3.56 (s, 2H),7.38-7.80 (m, 4H).

EXAMPLE 29 4-(1,1-Dimethyl-2-Methoxyethyl)Amino-2-(1-Imidazolyl)Quinazoline Dihydrochloride

[0411] A mixture of the compound prepared in Example 28 (165 mg, 0.62mmol), imidazole (169 mg, 2.48 mmol) and phenol (0.7 g) is heated at150° C. for 40 min. After cooling, the reaction mixture is diluted withethyl acetate, and washed with lN KOH and brine, and dried over MgSO₄.The filtrate is concentrated to leave a viscous oil, which is purifiedon 8 g of silica gel column eluting with 50% ethyl acetate in hexane toobtain the title compound (165 mg, 90% yield) as a colorless amorphous.(free base)

[0412] NMR (CDCl₃): delta 1.65 (s, 6H), 3.48 (s, 3H), 3.58 (s, 2H), 6.32(broad, 1H), 7.17 (s, 1H), 7.40 (m, 1H), 7.62-7.81 (m, 3H), 7.97 (s,1H), 8.67 (s, 1H).

[0413] To a solution of the compound above (160 mg, 0.54 mmol) inmethanol (2 ml) is added excess HCI-methanol solution (2 ml). Afterstirring for 20 min at room temperature, the reaction mixture isconcentrated. Excess HCI is evaporated with methanol (×3) to leave awhite solid. Trituration with ether gives the HCl salt (185 mg) as awhite powder. (HCl salt) (mp: 223°-225° C.).

[0414] NMR (200 MHz, DMSO-d6) delta: 9.80 (s, 1H), 8.59 (m, 1H), 8.34(m, 1H), 7.84-7.96 (m, 3H), 7.78 (m, 1H), 7.60 (m, 1H), 3.78 (s, 2H),3.29 (s, 3H), 1.57 (s, 6H). IR(KBr) nu: 1633, 1610, 1562,1520, 1474,1397, 1108, 754 cm⁻¹.

[0415] By the same procedure as described in Example 28 and Example 29,by using corresponding amine, the following compounds can be made:

[0416] 6-methoxy-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride;6-chloro-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride; 4-(3-ethoxypropyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride;6-nitro-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinehydrochloride;6-chloro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride; and6,7-dimethoxy-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazolinedihydrochloride.

EXAMPLE 30 6-Chloro-4-(2-Ethoxyethyl)Amino-2-(3-Pyridyl)Quinazoline

[0417] A solution of 2-(3-pyridyl)-4,6-dichloroquinazoline (1.0 g, 3.2mmol, prepared in Example 5(b)) and 2-methoxyethylamine (0.53 g, 7.0mmol) in 50 ml of ethanol is heated to reflux overnight. The solution isconcentrated, taken up in chloroform and water. After some mixing, thewater layer is found to be slightly acidic and is basified with sodiumcarbonate. The mixture is then agitated and separated. The organic layeris dried over potassium carbonate and concentrated. The concentrate ispurified on silica gel column with 5% methanol in chloroform as eluent.The product obtained is combined with additional material filtered fromthe aqueous layer, for a total of 0.35 g (1.1 mmol) of the titlecompound.

[0418] mp: 210°-212° C.

[0419] NMR (200 MHz, DMSO- d6 ): delta 3.32 (s, 3H), 3.67 (t, 211), 3.87(qd, 2H), 7.53 (m, 1H), 7.82 (s, 2H), 8.48 (s, 1H), 8.71 (m, 3H), 9.59(s, 1H)

[0420] IR (KBr): nu 3250 (m), 1692 (s), 1535 (s), 1430 (w), 1412 (w),1366 (m), 1140 (m), 823 (m) cm⁻¹.

[0421] To a mixture of 0.35 g (1.1 mmol) of the compound prepared abovein 5 ml of methanol is added 0.5 ml of 10% HCI in methanol. The solutionis concentrated to 1 ml, triturated in ether, filtered and dried undervacuum. Obtained 0.33 g (0.85 mmol) of the hydrochloride salt (mp: 190oC., (dec.)).

[0422] NMR (200 MHz, DMSO-d6) delta: 3.32 (s, 3H), 3.71 (t, 2H), 3.94(m, 2H), 8.01 (m, 2H), 8.12 (d, 1H), 8.75 (m, 1H), 9.01 (d, 1H), 9.20(d, 1H), 9.66 (s, 1H).

[0423] IR (KBr) nu: 3425, 2500-3050, 1633, 1610, 1569, 1387, 1107 cm⁻¹.

[0424] By the same procedure as described in Example 30, by usingcorresponding amine, the following compound can be obtained:

[0425] 6-chloro-4-(2-dimethylaminoethyl)amino-2-(3-pyridyl)quinazolinetrihydrochloride.

EXAMPLE 31 6-Hydroxy-4-Phenylmethylamino-2-(1-Imidazolyl)Quinazoline.

[0426] To 66 mg (0.2 mmol) of6-methoxy-4-phenylmethylamino-2-(1-imidazolyl)quinazoline dihyrochlorideprepared in Example 20 in 1 ml of acetic acid is added 0.8 ml (7 mmol)of 48% HBr in water. The mixture is heated below reflux for 23 hoursthen heated to full reflux for four hours. After cooling to roomtemperature, 15 ml of water is added to the solution, and theprecipitate is filtered and dried under vacuum. The material is purifiedon a preparative silica gel plate with 10% methanol in chloroform.Obtained 13 mg (41 mu mol) of the desired product as a solid. mp: 230°C., (dec.)

[0427] NMR (200 MHz, CD3OD) delta: 4.86 (s, 2H), 7.05 (s, 1H), 7.15-7.38(m, 4H), 7.40-7.50 (m, 3H), 7.58-7.66 (m, 1H), 7.92 (s, 1H), 8.52 (s,1H).

[0428] IR (KBr) nu: 3370, 3030, 2365, 1749, 1710, 1653, 1596, 1559,1523, 1488, 1465, 1407, 1376, 1291, 1244, 1162, 1098, 1060, 911,831cm⁻¹.

[0429] By the same procedure as described in Example 30, thehydrochloride of the title compound having the following physical datais given. (2HCl salt)

[0430] mp: 1550 C., (dec.)

[0431] NMR (200 MHz, DMSO-d6) delta: 4.92 (m, 2H), 7.22-7.77 (m, 8H),7.86 (s, 1H), 8.38 (s, 1H), 9.36 (m, 1H), 9.94 (s, 1H).

[0432] IR (KBr) nu: 3395-2640, 2365, 1734, 1628, 1607, 1567, 1542, 1473,1361, 1353, 1289, 1260, 1201, 1107, 1015, 835, 753, 702 cm⁻¹.

EXAMPLE 324-(2-(2-Hydroxyethoxy)Ethyl)Amino-6-Methylsulfinyl-2-(1-Imidazolyl)Quinazoline And Its Dihydrochloride

[0433] To 1.38 g of the4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline prepared in Example 20 dissolved in 10 ml of acetic acid isadded 4 ml of 30% hydrogen peroxide. The reaction is monitored by TLC.After stirring for {fraction (1/2 )} hour, the mixture is poured into 15g of 50% w/w sodium hydroxide and ice. The resulting mixture isextracted four times with chloroform, dried over anhydrous magnesiumsulfate and concentrated. The concentrate is triturated in ether andcollected to obtain 1.26 g of the desired product as a white solid.

[0434] To 400 mg of the compound prepared above in 10 ml of methanol isadded 1 ml of 10% HCl in methanol. After ten minutes, the mixture isconcentrated, triturated in ether and the solid collected to yield 441mg of the desired product as a dihyrochloride salt. (mp: 144°-147° C.).

[0435] NMR (200 MHz, DMSO-d6): d 2.85 (s, 3H), 3.50 (m, 4H), 3.70-3.90(m, 4H), 4.59 (m, 1H), 7.11 (s, 1H), 7.82 (m, 1H), 7.98 (s, 1H), 8.02(m, 1H), 8.62 (s, 1H), 8.67 (m, 1H), 9.14 (t, 1H). (2HCl salt) (mp:190°-192° C.).

[0436] NMR (200 MHz, DMSO-d6): d 2.89 (s, 3H), 3.51 (s, 4H), 3.76 (m,2H), 3.89(m, 2H), 7.90 (m, 2H), 8.14 (m, 1H), 8.45 (m, 1H), 8.89 (m,1H), 9.62 (t, 1H), 10.10 (m, 1H).

[0437] By the same procedure as described in Example 32, by usingcorresponding thioether, the following compounds can be obtained:

[0438]4-(2-methoxyethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline andits dihydrochloride, and6-methylsulfinyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinedihydrochloride.

EXAMPLE 334-(2-Methoxyethyl)Amino-6-Methylsulfonyl-2-(1-Imidazolyl)QuinazolineHydrochloride

[0439] To 0.63 g of the compound prepared in4-(2-methoxyethyl)amino-6-methylthio-2-(1-imidazolyl)quinazolineprepared in accordance with Example 20 (free base) in 7 ml of aceticacid is added 3 ml of 30% hydrogen peroxide solution and the mixture isstirred at room temperature for 17 hours. The mixture is then pouredinto a solution of 50% w/w sodium hydroxide in ice. The resultingmixture is extracted twice with 70 ml portions of chloroform, dried overanhydrous magnesium sulfate and concentrated. The concentrate istriturated in ether, and the solid collected to obtain 0.36 g of thedesired product as a white powder.

[0440] To a suspension of 300 mg of the compound above in 15 ml ofmethanol is added 1 ml of 10% HCl in methanol. The mixture becomesclear, then a precipitate formed. The mixture is concentrated toapproximately 5 ml, diluted with ether and filtered to obtain 319 mg ofthe desired product as a white solid.

[0441] mp: 241o-243o C. (HCI salt)

[0442] mp: 226o-228o C.

[0443] NMR (200 MHz, DMSO-d6): d 3.32(s, 3H), 3.36(s, 3H), 3.67(m, 2H),3.93(m, 2H), 7.81(s, 1H), 7.93(m, 1H), 8.30(m, 1I), 8.42(s, 1H), 9.16(m,1H), 9.72(t, 1H), 9.92(s, 1 H).

[0444] By the same procedure as described in Example 33,6-methylsulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazolinehydrochloride can be obtained.

[0445] mp: 125o-130o C.

[0446] NMR (200 MHz, DMSO-d6): delta 3.34(s, 3H), 4.97(d, 2H),7.31-7.50(m, 5H), 7.85(s, 1H), 7.93(d, 1H), 8.32(d, 1H), 8.44(s, 1H),9.14(s, 1H), 9.98(s, 1H), 10.12(t, 1H).

[0447] IR (KBr): nu 3230(s), 3040(s), 2705(s), 2370(m), 1616(s),1572(s), 1524(s), 1497(m), 1399(s), 1326(s), 1258(m), 1204(w), 1147(s),1008(m), 834(w), 783(s), 730(w), 620(w), 535(m)cm⁻¹.

EXAMPLE 346-Hydroxymethyl-4-Phenylmethylamino-2-(1-Imidazolyl)Quinazoline

[0448] To a suspension of 0.68 g of6-ethoxycarbonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline thecompound prepared in Example 19 in 50 ml of anhydrous tetrahydrofuran isadded 2 ml of 2M lithium borohydride in tetrahydrofuran. The reactionmixture is heated at reflux for two days. The mixture is thenconcentrated, diluted with water and the basic solution is acidifiedwith 1N hydrochloric acid. The resulting solution is then basified withpotassium carbonate, filtered and the solid washed with water andallowed to dry. The solid material is purified on silica gel columneluting with 5% methanol in chloroform, yielding 85 mg of the desiredproduct.

[0449] mp: 173o C. (dec.).

[0450] NMR (200 MHz, DMSO-d6): delta 4.67(d, 1H), 4.90(d, 1H), 5.47(t,1H), 7.23(m, 1H), 7.25-7.51(m, 5H), 7.67-7.85(m, 2H), 8.12(m, lH),8.34(m, 1H), 8.9 (s, H), 9.5 H).

[0451] IR (KBr): nu 3445(mw), 2365(mw), 1599(s), 1559(m), 1505(mw),1444(w), 1410(m), 1340(w), 1161(w), 1073(w)cm⁻¹.

[0452] By the same procedure as described in Example 34, the followingcompounds can be obtained.

[0453]4-(2-methoxyethyl)amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline, and

[0454]4-[2-(2-hydroxyethoxy)ethyl]amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline.

EXAMPLE 35 6-Iodoquinazolin-2,4-Dione

[0455] To a mixture of 25.36 g of 2-amino-5-iodobenzoic acid in 250 mlof water and 90 ml of THF is added 7.40 g of glacial acetic acid andstirred at room temperature. Then 7.82 g of potassium cyanate in waterdropwise, and the mixture is left overnight. Another 5.47 g of potassiumcyanate is added, and the mixture is stirred overnight. A total of 160 gof NaOH pellets are added portionwise, keeping the mixture cool inice-water bath. The mixture is stirred at room temperature overnight.The mixture is cooled in a refrigerator and the precipitate filteredthrough a sintered glass funnel. The precipitate is then dissolved inwater and acidified with 4N HCl. The precipitate is collected byfiltration. The solid is dried in a vacuum oven to yield 25.44 g of thetitle compound.

EXAMPLE 36 6-(2-Triethylsilylethylnyl)Quinazolin-2,4-Dione

[0456] In a flask is placed 0.544 g of triphenylphosphine, 0.184 g ofpalladium chloride, and 5 ml of diethylamine. Stirred under a nitrogenatmosphere. To the resulting yellow mixture is added 75 ml ofdiethylamine, followed by 10.02 g of the compound prepared in Example35. Then 19.8 mg of cuprous iodine is added to the purple suspension,which turns gray after 10 minutes. After 0.5 hr, 5.36 g of triethylsilylacetylene and stirred at room temperature. After 3 hrs the solutionturns purple. After another 1.5 hours, the solution turns brown and isleft to stir overnight. The solvent is removed under reduced pressure at40° C. and water is added. The mixture is acidified with 1N—HCI. Theprecipitated solid is collected by filtration, washed with water, anddried in a vacuum oven. The solid is then passed through a silica gelcolumn, eluting with THF. After drying yielded 10.22 g of the titlecompound having the following physical data.

[0457] NMR (200 MHz, DMSO-d6): delta 0.65(dd, 6H), 0.93(dd, 9H), 7.15(d,1H), 7.69(d, 1H), 11.38(br, 2H).

EXAMPLE 37 2,4-Dichloro-6-(2-Triethylsilylethylnyl)(Quinazoline

[0458] To 5.09 g of the compound prepared in Example 36, is added 25 mlof POCl₃ and warmed. Then added 1.03 g of N,N-dimethylaniline and heatedto reflux. After 3.5 hrs, the excess POCl₃ is removed under reducedpressure, and the residue diluted in chloroform and poured slowly overice. The organic layer is collected and the solvent removed. The residueis passed through a silica gel column using 20% EtOAc/hexane as asolvent, yielding 1.4 g of the product having the following physicaldata.

[0459] NMR (200 MHz, CDCl3): delta 0.72(m, 6H), 1.00(m, 9H), 7.98(d,1H), 8.33(s, 1H).

EXAMPLE 382-Chloro-4-(2-Methoxyethyl)Amino-6-(2-Triethylsilylehnyl)Quinazoline

[0460] To 1.4 g of the compound prepared in Example 37 in 20 ml ofchloroform is added 2-methoxyethylamine and stirred at room temperaturefor 1.5 hr. Then 4.2 ml of 1N—NaOH is added, the mixture is heated toreflux, and is left to reflux overnight. The solvent is removed underreduced pressure, and the residue taken up in chloroform and water. Theorganic layer is collected and dried over anhydrous potassium carbonate.Removal of solvent under reduced pressure yields 1.44 g of the titlecompound.

[0461] NMR (200 MHz, CDCl3): delta 0.73 (m, 6H), 1.07(m, 9H), 3.45(s,3H), 3.69(t, 2H), 3.8a(dd, 2H), 6.32(br, 1H), 7.69(d, 1H), 7.7a(dd, 1H),7.80(s, 1H).

EXAMPLE 39 2-( -Imidazolyl)-4-(2-Methoxyethyl)Amino-6-(2-Triethylsilylethynyl) Quinazoline

[0462] To 1.32 g of the compound prepared in Example 38 in 5 ml ofethanol is added excess imidazole (0.93 g) and heated in an oil bath to115° C. After 1.5 hours, the mixture is removed from heat and diluted inchloroform and washed with 1N—NaOH, collected the organic layer andwashed with water. The organic layer is extracted and dried overanhydrous potassium carbonate. Removal or solvent yields 1.33 g of thetitle compound.

[0463] mp: 158°-160° C.

[0464] NMR (200 MHz, DMSO-d6): delta 0.70(q, 6H), 1.0S(t, 9H), 3.30(s,3H), 3.64(t, 2H), 3.81 (dd, 2H), 7.10(s, 1H), 7.65(d, 1H), 7.78(dd, 1H),7.96(s, 1H), 8.01 (s, 1H), 8.60(s, 1H), 8.95(br, 1H).

[0465] By the same procedures as described in Examples 35-38, andExample 39, the following compound is obtained:2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-(2-triisopropylsilylethynyl)quinazoline

[0466] mp: 155°-156° C.;

[0467] NMR (200 MHz, CDCl3): delta 1.09 (s, 3H), 1.16 (s, 18H), 2.28(br, 1H), 3.70 (m, 2H), 3.84 (dd, 4H), 3.95 (t, 2H), 6.65 (br, 1H), 7.14(s, 1H), 7.68 (d, 1H), 7.75 (dd, 1H), 7.87 (s, 1H), 7.93 (s, 1H), 8.65(s, 1H).

EXAMPLE 40 6-Ethynyl-4-(2-Methoxyethyl)Amino-2-(1-Imidazolyl)Quinazoline

[0468] To 1.35 g of the compound prepared in Example 39 in 20 ml of THEis added 3.3 ml of tetrabutylammonium fluoride (1M in TIE), and isstirred at room temperature for 1.5 hrs. The excess THF is removed underreduced pressure, and the residue taken up in chloroform and water. Theinsoluble precipitate is collected by filtration, yielding 0.83 g of thetitle compound.

[0469] NMR (200 MHz, DMSO-d6): delta 3.33(s, 3H), 3.66(m, 2H), 3.83(m,2H), 4.34(s, 1H), 7.11 (s, 1H), 7.65(d, 1H), 7.82(dd, 1H), 7.96(s, 1H),8.57(d, 1H), 8.62(s, 1H), 8.90(broad, 1H).

[0470] IR (KBr): nu 3290(s), 2945(m), 1606(s), 1559(s), 1451(s),1352(s), 1106(s), 835(s) cm⁻¹.

[0471] By the same procedure, the following compound is given:

[0472]2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-ethynylquinazolineand its salt.

EXAMPLE 41 6-Acetyl-4-(2-Methoxyethyl)Amino-2-(1-Imidazolyl)Quinazoline

[0473] To 0.541 g of the compound prepared in example 18 in 10 ml ofacetic acid is added 0.7 ml of 10% H₂SO₄ and 0.10 g of mercury IIsulfate and heated to reflux. After 2 hours, the solution is removedfrom heat and basified. The yellow precipitate is filtered. The solid iswashed with THE and the solvent is removed under reduced pressure andthe residue titrated in 50% ether/pentane. The solid is collected byfiltration. Yielded 0.063 g of the desired product.

[0474] mp: 208°-210° C.

[0475] NMR (200 MHz, CDCl3): delta 2.64(s, 3H), 3.49(s, 3H), 3.79(t,2H), 3.95(q, 2H), 7.00(broad, 1H), 7.16(t, 1H), 7.74(d, 1H), 7.95(t,1H), 8.17(dd, 1H), 8.42(d, 1H), 8.67(t, 1H).

[0476] By the same procedure as described in Example 41,4-[2-(2-hydroxyethoxy) ethyl]amino-6-acetyl-2-(1-imidazolyl)quinazolinecan be obtained.

[0477] It will be understood that various changes and modifications canbe made in the details of procedure, formulation and use withoutdeparting from the spirit of the invention, especially as defined inthe,following claims.

We claim:
 1. A method for inhibiting the growth of neoplastic cellscomprising exposing the cells to a growth inhibiting effective amount ofa compound of Formula I:

R₁ is hydrogen or C1-4 alkyl; Y is C1-6 alkylene; A is —O—R₀ or—S(O)_(p)—R₀, R₀ is C1-4 alkyl-hydroxy; p is 0-2; Z is single bond,methylene, ethylene (CH₂CH₂), vinylene (CH═CH) or ethynylene (C═C); CyBis: (1) 7-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one, two or three nitrogenatoms, (2) 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, two or three nitrogen atoms, (3)6-membered, unsaturated or partially saturated, monocyclic hetero ringcontaining as hetero atoms, one nitrogen atom, (4) 4- or 5-membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one, two or three nitrogen atoms, or (5) 4-7 membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one or two oxygen atoms, or one or two sulfur atoms; R₃ ishydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl; R₄ is (1)hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) —COOR₈, in which R₈ ishydrogen or C1-4 alkyl, (5) —NR₉R₁₀, (6) —NHCOR₁₁, (7) —NHSO₂R₁₁, (8)SO₂NR₉R₁₀, (9) —OCOR₁₁, (10) halogen, (11) trifluoromethyl, (12)hydroxy, (13) nitro, (14) cyano, (15) —SO₂N═CHN R₁₁R₁₀, (16) —CONR₁₂R₁₃,(17) C1-4 alkylthio, (18) C1-4 alkylsulfinyl, (19) C1-4 alkylsulfonyl,(20) ethynyl, (21) hydroxymethyl, (22) tri(C1-4 alkyl) silylethynyl or(23) acetyl; and m and n independently are 1 or 2; with the proviso thata CyB ring should not bond to Z through a nitrogen atom in the CyB ringwhen Z is vinylene or ethynylene; R₉ is hydrogen, C1-4 alkyl orphenyl(C1-4 alkyl); R₁₀ is hydrogen or C1-4 alkyl; R₁₁ is C1-4 alkyl;R₁₂ is hydrogen or C1-4 alkyl; R₁₃ is C1-4 alkyl or phenyl(C1-4 alkyl);or pharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable salts, or hydrates thereof.
 2. The method of claim 1 whereinthe compound is selected from the group consisting of4-[2-(2-hydroxyethoxy)ethyl]amino-6-acetyl-2-(1-imidazolyl)quinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-ethynylquinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-(2-triisopropylsilylethynyl)quinazoline,4-[2-(2-hydroxyethoxy)ethyl]amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline,6-chloro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazoline,4- [2-(2-hydroxyethoxy)ethyl]amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolineor6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazoline,and pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 3. Amethod of treating a mammal having precancerous lesions comprisingadministering a pharmacologically effective amount of a compound ofFormula I:

R₁ is hydrogen or C1 -4 alkyl; Y is C1-6 alkylene; A is —O—R₀ or—S(O)_(p)—R₀, R₀ is C1-4 alkyl-hydroxy; p is 0-2; Z is single bond,methylene, ethylene (CH₂CH₂), vinylene (CH═CH) or ethynylene (C═C); CyBis: (1) 7-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one, two or three nitrogenatoms, (2) 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, two or three nitrogen atoms, (3)6-membered, unsaturated or partially saturated, monocyclic hetero ringcontaining as hetero atoms, one nitrogen atom, (4) 4- or 5-membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one, two or three nitrogen atoms, or (5) 4-7 membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one or two oxygen atoms, or one or two sulfur atoms; R₃ ishydrogen, C1-4 alkyl, C1-4 alkoxy, halogen or trifluoromethyl; R₄ is (1)hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) —COOR₈, in which R₈ ishydrogen or C1-4 alkyl, (5) —NR₉ R₁₀, (6) —NHCOR₁₁, (7) —NHSO₂R₁₁, (8)SO₂NR₉R₁₀, (9) —OCOR₁₁, (10) halogen, (11) trifluoromethyl, (12)hydroxy, (13) nitro, (14) cyano, (15) —SO₂N═CHN R₁₁R₁₀, (16) —CONR₁₂R₁₃,(17) C1-4 alkylthio, (18) C1-4 alkylsulfinyl, (19) C1-4 alkylsulfonyl,(20) ethynyl, (21) hydroxymethyl, (22) tri(C1-4 alkyl) silylethynyl or(23) acetyl; and m and n independently are 1 or 2; with the proviso thata CyB ring should not bond to Z through a nitrogen atom in the CyB ringwhen Z is vinylene or ethynylene; R₉ is hydrogen, C1-4 alkyl or phenyl(C1-4 alkyl); R₁₀ is hydrogen or C1-4 alkyl; R₁₁ is C1-4 alkyl; R₁₂ ishydrogen or C1 -4 alkyl; R₁₃ is C1-4 alkyl or phenyl(C1-4 alkyl); orpharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable salts, or hydrates thereof.
 4. The method of claim 3 whereinthe compound is selected from the group consisting of4-[2-(2-hydroxyethoxy)ethyl]amino-6-acetyl-2-(1-imidazolyl)quinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-ethynylquinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-(2-triisopropylsilylethynyl)quinazoline,4-[2-(2-hydroxyethoxy)ethyl]amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline,6-chloro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazoline,4-[2-(2-hydroxyethoxy)ethyl]amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazolineor6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazoline,and pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.
 5. Amethod for regulating apoptosis in human cells comprising exposing saidcells to an effective amount of a compound of Formula I:

R₁ is hydrogen or C1-4 alkyl; Y is C1-6 alkylene; A is —O—R₀ or—S(O)_(p)—R₀, R₀ is C1-4 alkyl-hydroxy; p is 0-2; Z is single-bond,methylene, ethylene (CH₂CH₂), vinylene (CH═CH) or ethynylene (C═C); CyBis: (1) 7-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, one, two or three nitrogenatoms, (2) 6-membered, unsaturated or partially saturated, monocyclichetero ring containing as hetero atoms, two or three nitrogen atoms, (3)6-membered, unsaturated or partially saturated, monocyclic hetero ringcontaining as hetero atoms, one nitrogen atom, (4) 4- or 5-membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one, two or three nitrogen atoms, or (5) 4-7 membered,unsaturated or partially saturated, monocyclic hetero ring containing ashetero atoms, one or two oxygen atoms, or one or two sulfur atoms; R₃ ishydrogen, C1 -4 alkyl, C1 -4 alkoxy, halogen or trifluoromethyl; R₄ is(1) hydrogen, (2) C1-4 alkyl, (3) C1-4 alkoxy, (4) —COOR₈, in which R₈is hydrogen or C1-4 alkyl, (5) —NR₉ R₁₀, (6) —NHCOR₁₁, (7) —NHSO₂R₁₁,(8) SO₂NR₉R₁₀, (9) —OCOR₁₁, (10) halogen, (11) trifluoromethyl, (12)hydroxy, (13) nitro, (14) cyano, (15) —SO₂N═CHN R₁₁R₁₀, (16) —CONR₁₂R₁₃,(17) C1-4 alkylthio, (18) C1-4 alkylsulfinyl, (19) C1-4 alkylsulfonyl,(20) ethynyl, (21) hydroxymethyl, (22) tri(C1-4 alkyl) silylethynyl or(23) acetyl; and m and n independently are 1 or 2; with the proviso thata CyB ring should not bond to Z through a nitrogen atom in the CyB ringwhen Z is vinylene or ethynylene; R₉ is hydrogen, C1-4 alkyl orphenyl(C1-4 alkyl); R₁₀ is hydrogen or C1-4 alkyl; R₁₁ is C1-4 alkyl;R₁₂ is hydrogen or C1-4 alkyl; R₁₃ is C1-4 alkyl or phenyl(C1-4 alkyl);or pharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable salts, or hydrates thereof.
 6. The method of claim 5 whereinthe compound is selected from the group consisting of: 4-[2-(2-hydroxyethoxy)ethyl]amino-6-acetyl-2-(1-imidazolyl)quinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-ethynylquinazoline,2-(1-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-6-(2-triisopropylsilylethynyl)quinazoline,4-[2-(2-hydroxyethoxy)ethyl]amino-6-hydroxymethyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfinyl-2-(1-imidazolyl)quinazoline,6-chloro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazoline,4-[2-(2-hydroxyethoxy)ethyl]amino-6-methoxycarbonyl-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylthio-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(1-imidazolyl)quinazoline,4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)-5,6,7,8-tetrahydroquinazoline or6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-²-(1-imidazolyl)quinazoline,and pharmaceutically acceptable acid addition salts thereof,pharmaceutically acceptable salts thereof, or hydrates thereof.